García-Guerrero et al described their laboratory study where myeloma cells from 12 patients were treated with titrated doses of panobinostat (0, 10 and 25nM). In order to assess CD38 expression, the authors used flow cytometry after exposure to panobinostat. The authors then went on to assess whether an increase in CD38 expression caused by panobinostat would augment the anti-myeloma activity of the anti-CD38 monoclonal antibody daratumumab. To do this they treated primary myeloma cells from 4 patients with panobinostat for 48 hours at a dose of 10nM and then added either daratumumab or a control antibody as well as patient-derived autologous peripheral blood mononuclear cells (PBMCs) to initiate antibody-dependent cellular cytotoxicity (ADCC).
Flow cytometry demonstrated a uniform increase in CD38 expression with upregulation detectable by 24 hours. Upregulation peaked at 48 hours post treatment and had a higher peak with a 25nM (5 fold higher than untreated) dose than the 10nM dose (3 fold higher than untreated). Significantly, the increase in CD38 expression was equal in both newly diagnosed as well as relapsed/refractory (but daratumumab naive) patients. The effect on expression was also observed to be rapidly reversible and returned to baseline within 24 hours of withdrawing the drug. On re-treatment the expression increased in the same manner and to the same level as during the initial exposure. Lymphoma cells used as controls demonstrated no CD38 upregulation in response to panobinostat.
In assessing the effect of panobinostat on the anti-myeloma activity of daratumumab, the authors found that there was a significant increase in ADCC in the panobinostat treated cells. An average of 78% of the panobinostat-treated myeloma cells were eliminated by daratumumab within the 4 hour ADCC assay, whereas only 51% of the non-panobinostat treated cells were eliminated.
Overall the authors suggest that this data supports the previous findings in other studies suggesting that CD38 expression is an important factor in daratumumab mediated ADCC. It also supports the hypothesis that panobinostat can be used to increase CD38 expression and that following on from this there is evidence that panobinostat may augment the anti-myeloma activity of daratumumab. The data suggests that panobinostat and daratumumab may be used synergistically to increase and extend duration of response when compared to daratumumab alone. This suggests the need for formal clinical trials to investigate the potential for using panobinostat and daratumumab combination therapy in the treatment of multiple myeloma.